Cellulose dialysis membranes for hemodialysis in the form of flat films, tubular films or hollow filaments have been known for a lengthy period and are still preferably employed in artificial kidneys. However, it has not yet been possible to eliminate some properties which give rise to complaints.
Thus German Pat. No. 2,705,735 discloses a dialysis membrane for hemodialysis, having antithrombogenic compounds chemically bonded thereto, the dialysis membrane consisting of two or more layers of a cellulose re-generated from cuprammonium cellulose solution, each of which has been obtained from separately fed orifices of a spinneret, which cellulose contains chemically bonded substances having antithrombogenic activity.
However, it has also been proposed in German Offenlegungsschrift No. 1,720,087 that by reacting the polymeric material of the membrane with an alkyl halide and then reacting the resulting material with an alkali metal salt of an antithrombogenic compound having a cationic residue (for example heparin or a heparinoid compound) the risk of blood coagulation is diminished. The possible alkyl halides in this context also include haloalkyldialkylamines. Moreover cellulose, but most importantly cellulose acetate, is among the possible polymers.
An antithrombogenic effect of these known dialysis membranes is observed only when the degree of substitution of the modified cellulose is high, i.e., greater than at least 0.1, and a preheparinization with a relatively high heparin concentration (0.1 to 1% by weight solutions) is carried out in a separate stage.
German Offenlegungsschrift No. 3,524,596 has already disclosed a dialysis membrane with improved biocompatibility, which is distinguished in that the mean degree of substitution of a modified cellulose is 0.02 to 0.07. The known dialysis membrane composed of modified cellulose preferably contains such a modified cellulose which has a structure represented by the formula EQU cellulose-R'-X-Y
where
X represents --NR"-- and/or --N.sup.+ R".sub.2 -- and/or --S-- and/or --SO-- and/or --SO.sub.2 - and/or --CO--NR-- and/or --CO--O-- and/or --0--, PA0 Y represents --R and/or --NR.sub.2 and/or --Si(OR")3 and/or --SO.sub.3 H and/or --COOH and/or --PO.sub.3 H.sub.2 and/or --N.sup.+ HR.sub.2 and the salts thereof, PA0 R' represents an alkylene group and/or cycloalkylene group and/or arylene group having a total of 1 to 25 C atoms, PA0 R" represents a hydrogen atom or R, and PA0 R represents an alkyl group having 1 to 5 C atoms and/or a cycloalkyl group and/or aryl group.
This known dialysis membrane is capable of reducing to a considerable extent blood coagulation, leukopenia and complement activation. However, no noteworthy extent of adsorption of beta-2-microglobulin has been detected.
Apart from the circumstance that dialysis membranes composed of synthetic or natural polymers can, when used in artificial kidneys, very easily induce blood coagulation, which is substantially prevented by appropriate drug treatment, in the case of dialysis membranes composed of regenerated cellulose there is frequently a transient fall in leukocytes in the first period of dialysis treatment when a kidney patient is treated with dialyzers having cellulose membranes. This effect is called leukopenia. Leukopenia is a reduction in the number of leukocytes (white blood corpuscles) in the circulating blood. The number of white blood corpuscles in humans is about 4,000 to 12,000 cells/mm.sup.3.
Leukopenia associated with dialysis is most pronounced 15 to 20 minutes after the start, it being possible for the neutrophils (which are the leukocytes which can be stained with neutral or simultaneously with acidic and basic dyes) to disappear almost completely. Subsequently, the number of leukocytes recovers again within about one hour to almost the initial level or exceeds it.
If, after the leukocytes have recovered, a new dialyzer is connected, leukopenia occurs again to the same extent.
Cellulose membranes cause pronounced leukopenia. Even though the clinical significance of leukopenia has not been scientifically elucidated, there is nevertheless a desire for a dialysis membrane for hemodialysis which does not exhibit the leukopenic effect, without this adversely affecting the other very desired properties of dialysis membranes composed of regenerated cellulose.
During hemodialysis using membranes composed of regenerated cellulose, beside the leukopenia there has also been found a distinct complement activation. The complement system within the blood serum is a complex plasma-enzyme system which consists of many components and acts in various ways to prevent damage due to invading foreign cells (bacteria, etc.). When antibodies against the invading organism are present, there can be complement specific activation by .The complex of the antibodies with antigenic structures of the foreign cells, otherwise complement activation takes place by an alternative pathway due to special surface features of the foreign cells. The complement system is based on a multiplicity of plasma proteins. After activation, these proteins react specifically in a defined sequence with one another and, finally, a cell-damaging complex which destroys the foreign cell is formed.
Individual components release peptides which induce inflammatory manifestations and occasionally can also have undesired pathological consequences for the organism. It is assumed that in the case of hemodialysis membranes composed of regenerated cellulose the activation takes place by the alternative pathway. These complement activations are detected objectively by determination of the complement fragments C3a and C5a.
In this context, reference is made to the following studies: D. E. Chenoweth et al., Kidney International vol. 24, pages 746 et seq., 1983 and D. E. Chenoweth, Asaio-Journal vol. 7, pages 44 et seq., 1984.
The carpal tunnel syndrome is but little affected by the known modified dialysis membranes. This is why there is a considerable need for further modifications of the cellulose in order to eliminate this phenomenon too.